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Transcript
Lecture 15 B Cell Activation and Antibody Production Overview of B Cell Development, Activation, Antibody Production B Cell Antigens Antigens Thymus Dependent Antigens Thymus Independent Antigens Dependent Upon Helper T Cells Does Not Need Helper T Cells to Induce Antibody Production to Induce Antibody Production Proteins Polysaccharides, Lipids B Cell Responses to ThymusDependent Antigens (T CellDependent Antibody Responses) Primary and Secondary Antibody Responses Phases of the Humoral Immune Response A T-Dependent Antigen Must Contain Both B and T Cell Epitopes Antigen T Cell Epitope B Cell Epitope LINKED RECOGNITION Follicles (B Cells) (T Cells) Activation of B Cells by Antigen and Complement 1. Biochemical Signals 2. Endocytosis of Antigen Antigen Recognition Phase of T-Dependent Antibody Response Interactions of B Cells with Helper T Cells TEM Picture B Cell B Cell T Cell Initial Contact T-B Conjugate Note the broad area of membrane contact between B and T Cells. Helper T Cell-Dependent Activation Of B Lymphocytes B-Cell Activation by Thymus-Dependent Antigens C’R Cytokines Linked Recognition Activated B Cells (Following Interaction with TH Cells Extra-follicular Site Antibody Secreting Cells Antibodies Follicle Germinal Center Late Events in T Cell-Dependent Antibody Responses-Germinal Center Reaction • Affinity Maturation – Somatic Hypermutation • Generation of Memory B Cells Somatic Hypermutation and Affinity Maturation of Antibodies Affinity maturation is the process that leads to increased affinity of antibodies for a particular antigen as a result of somatic mutation in the Ig genes followed by selective survival of B cells producing the antibodies with the highest affinity Affinity Maturation in Antibody Responses Selection of High Affinity B Cells in Germinal Center Phases of the Humoral Immune Response to T-Dependent Antigen Anatomy of Humoral Immune Responses Antibody Isotype Switching Isotype Switching Under the Influence of Helper T Cell-Derived Cytokines Mechanism of Ig Isotype Switching CD4 T Cell-Dependent Effects in Antibody Responses • Memory B Cell Development • Isotype Switching • Affinity Maturation ThymusIndependent Antigens B-Cell Activation by Thymus-Independent and Dependent Antigens Most TI antigens are polyvalent and induce maximal Crosslinking of membrane Ig on B cells, without a Need for T cell help. Features of Antibody Responses to T-Dependent and T-Independent Antigens Antibody Response to T-Dependent Antigens • Role of Helper T Cells – Cytokines – CD40/CD40L interactions • Isotype Switching – Switch Recombination – Cytokines and Isotypes • Affinity Maturation – Somatic hypermutation – Selection for B cells which produce High Affinity Antibodies • Memory B Cells Antibody Effector Functions Effector Functions of Antibodies Neutralization of Microbes by Antibodies Neutralization of Toxins by Antibodies Opsonization of Microbes by Antibodies Antibody-Dependent Cellular Cytotoxicity (ADCC) Functions of Complement Complement-Mediated Lysis of E. coli Alive Killed Cellular Interactions in Immune Responses The Immune Response: A Summary WHY can immune system recognize so many different epitopes?? Antibody heavy and light chains are composed of gene segments Variable regions are unique A limited variety of constant region sequences are used They must be rearranged into functional genes before they can be transcribed p. 106 Organization of Ig genes Germline DNA- gene segments surrounded by noncoding regions These are rearranged to form functional genes Light chains- V, J and C segments Heavy chain- V, D, J, C V regions rearrange first A single V can rearrange to more than one C Multigene families or In humans: 40 V, 5 J, 1 C Similar number of genes in humans; this is rare in mice Heavy-chain gene families are similar but more complex (D segment) CH regions formed from exons p. 111 One of many possible combinations Heavy chain DNA D-J and V-DJ rearrangements must occur separately On a mature B cell, both mIgM and mIgD are expressed on the cell surface How does rearrangement occur? Each V, D and J is flanked by RSS (Recombination signal sequences) Mechanism is controlled by RAG-1 and RAG-2 proteins and an enzyme TdT If any of these proteins is defective no mature B cells can form; nor T cells p. 112 “Junctional flexibility” contributes to diversity p. 115 But not all rearrangements are “productive” B cells are diploid and contain chromosomes from both parents However, heavy chain genes are rearranged from only one chromosome, as are light chain genes. Therefore, any one B cell will contain one VH and one VL (antigen specificity) How? Allelic exclusion (Yancopoulos and Alt, 1986) Model for allelic exclusion p. 116 Generation of antibody diversity (why are there so many possible antigen combining sites?) Multiple germline gene segments In human germline: 51 VH, 27 D, 6 JH 40 V, 5 J 30 V , 4 J Combinatorial V-J and V-D-J joining 57 V X 27 D X 6 J= 8262 possible combinations for VDJ joining 40 V X 5J = 200 possible V 120 possible V 8262 X (200+120) = 2.64 X 106 possible combinations Without taking into account other sources of diversity Junctional flexibility in V-J or V-D-J junction Additional nucleotides added at junctions (P or N addition), if a single-stranded region is created during the joining process Somatic hypermutation mutations occur AFTER rearrangement tends to occur in CDR regions affects antigen affinity (tends to increase): “affinity maturation” occurs in B but not T cells Class switching After antigen stimulation heavy-chain DNA can rearrange so VDJ joins to any isotype Cytokines help determine the isotype IgG2a or IgG3 (mice): IFN- IgM: IL-2, IL-4, IL-5 IgE: IL-4 p. 122 Membrane-bound or secreted? Alternative splicing, p. 124 Mature B cells express both mIgM and mIgD No switch site between C and C The VDJCC contains 4 polyadenylation sites mIgM or mIgD can be generated depending on which polyadenylation site is used Regulatory elements of transcription Promoters Enhancers Gene silencers Gene rearrangement brings enhancers close to the promoter they influence Why aren’t Igs produced in B cells? In T cells a protein may bind to the -enhancer and prevent V-J joining Arrangement of immunoglobulin genes (and formation from exons) and greatly facilitated formation of genetically engineered antibodies